2. Academic Validation
  3. Discovery and Optimization of Rationally Designed Bicyclic Inhibitors of Human Arginase to Enhance Cancer Immunotherapy

Discovery and Optimization of Rationally Designed Bicyclic Inhibitors of Human Arginase to Enhance Cancer Immunotherapy

  • ACS Med Chem Lett. 2020 Mar 23;11(4):582-588. doi: 10.1021/acsmedchemlett.0c00058.
Matthew J Mitcheltree 1,  Derun Li 1,  Abdelghani Achab 1,  Adam Beard 1,  Kalyan Chakravarthy 1,  Mangeng Cheng 1,  Hyelim Cho 1,  Padmanabhan Eangoor 1,  Peter Fan 1,  Symon Gathiaka 1,  Hai-Young Kim 1,  Charles A Lesburg 1,  Thomas W Lyons 1,  Theodore A Martinot 1,  J Richard Miller 1,  Spencer McMinn 1,  Jennifer O'Neil 1,  Anandan Palani 1,  Rachel L Palte 1,  Josep Saurí 1,  David L Sloman 1,  Hongjun Zhang 1,  Jared N Cumming 1,  Christian Fischer 1
Affiliations

Affiliation

  • 1 Discovery Chemistry; Quantitative Biosciences; Pharmacokinetics, Pharmacodynamics, and Drug Metabolism; Computational and Structural Chemistry; Analytical Research and Development; Process Research and Development; Oncology Discovery; and External Discovery Chemistry, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
PMID: 32292567 DOI: 10.1021/acsmedchemlett.0c00058
Abstract

The action of Arginase, a metalloenzyme responsible for the hydrolysis of arginine to urea and ornithine, is hypothesized to suppress immune-cell activity within the tumor microenvironment, and thus its inhibition may constitute a means by which to potentiate the efficacy of immunotherapeutics such as anti-PD-1 checkpoint inhibitors. Taking inspiration from reported enzyme-inhibitor cocrystal structures, we designed and synthesized novel inhibitors of human Arginase possessing a fused 5,5-bicyclic ring system. The prototypical member of this class, 3, when dosed orally, successfully demonstrated serum Arginase inhibition and concomitant arginine elevation in a syngeneic mouse carcinoma model, despite modest oral bioavailability. Structure-based design strategies to improve the bioavailability of this class, including scaffold modification, fluorination, and installation of active-transport recognition motifs were explored.

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